4β-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4β-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist

In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino (5b–e), or 7α-dialkylamino (5f–h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties

Synthesis and Evaluation of Metabotropic Glutamate Receptor Subtype 5 Antagonists Based on Fenobam

In an effort to discover potent and selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonists, 15 tetrahydropyrimidinone analogues of 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-4,5-dihydro-1<i>H</i>-imidazol-2-yl)-urea (fenobam) were synthesized. These compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The IC₅₀ value for 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-1,4,5,6-tetrahydropyridine)­urea (<b>4g</b>) was essentially identical to that of fenobam

4β-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4β-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist

In previous studies we reported that addition of 7α-acylamino groups to <i>N</i>-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)­morphan (<b>4</b>) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (<b>5a</b>), 7α-alkylamino (<b>5b</b>–<b>e</b>), or 7α-dialkylamino (<b>5f</b>–<b>h</b>) group to <b>4</b> leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue <b>5h</b> was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure nonselective opioid receptor antagonist <i>N</i>-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)­morphan (<b>4</b>) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino, or 7α-dialkylamino group to <b>4</b> leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties

Design, Synthesis, and Biological Evaluation of Structurally Rigid Analogues of 4‑(3-Hydroxy­phenyl)­piperidine Opioid Receptor Antagonists

In order to gain additional information concerning the active conformation of the <i>N</i>-substituted <i>trans</i>-3,4-dimethyl-4-(3-hydroxy­phenyl)­piperidine (<b>1</b>) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid <i>N</i>-substituted-6-(3-hydroxy­phenyl)­3-azabicyclo­[3.1.0]­hexane and 3-methyl-4-(3-hydroxy­phenyl)-4-azabicyclo­[4.1.0]­heptanes. Evaluation of the conformationally constrained series in a [³⁵S]­GTPγS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to <b>1</b>. The studies of the rigid compounds also suggested that the 3-methyl group present in compound <b>1</b> type antagonists may not be necessary for their pure opioid antagonist properties

N-Ammonium Ylide Mediators for Selective Electrochemical C–H Oxidation

The site-specific oxidation of strong C(sp3)-H bonds is of uncontested utility in organicsynthesis. From simplifying access to metabolites and late-stage diversification of lead compoundsto truncating retrosynthetic plans, there is a growing need for new reagents and methods forachieving such a transformation in both academic and industrial circles. One main drawback ofcurrent chemical reagents is the lack of diversity with regards to structure and reactivity thatprevent a combinatorial approach for rapid screening to be employed. In that regard, directedevolution still holds the greatest promise for achieving complex C–H oxidations in a variety ofcomplex settings. Herein we present a rationally designed platform that provides a step towardsthis challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific,chemoselective C(sp3)–H oxidation. By taking a first-principles approach guided by computation,these new mediators were identified and rapidly expanded into a library using ubiquitous buildingblocks and trivial synthesis techniques. The ylide-based approach to C–H oxidation exhibitstunable selectivity that is often exclusive to this class of oxidants and can be applied to real worldproblems in the agricultural and pharmaceutical sectors.</p

4β-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4β-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist

In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino (5b–e), or 7α-dialkylamino (5f–h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties